Promoters & Inhibitors of the Metabolic & Antioxidative Pathway of PGC-1a and Its Role in Environmental Illness

When you are talking about biological pathways there is never a linear path where one protein action only leads to another. It would make understanding these pathways alot simpler but it just does not work that way. Of course, if this were so, it would be so easy for everything to just stop working if something went wrong. When there are multiple pathways that intersect, run parallel or make feedback loops on proteins that ultimately activate other proteins, it results in a kind of "checks and balance system" inside a cell. This provides a safety mechanism so processes keep working or at least "keep chugging along" even if one protein or even a few proteins that make up a pathway are damaged, are lost or their signals get misdirected. It is easy to get confused when thinking about all those protein interactions at the same time. For me.... it is easier to break the activities down and focus on the processes individually. It makes it easier to understand how these pathways work and easier to remember just what they do! (If you would like to see a graphical depiction of the tangled mess these pathways make - click here!) Today's focus is on mostly on the PGC1a pathway and its relevance to the molecular biology of environmental illnesses.

In a recent blog, I wrote about my interest in nutrition as well as, a variety of other topics I have studied that impact health and wellness. In that blog, I discussed how a number of dietary excesses or deficiencies may influence environmental disease. Specifically dietary deficiencies include vitamin D, vitamin B and folate and also may include methionine(either too little or too much). I added changes in human dietary patterns and lifestyles over the last several decades or more may have contributed to this. There is debate on whether we get too much or too little methionine from our diet. The most recent articles provide evidence that methionine actually increases mitochondrial stress and lack of DNA repair even though others recommend supplementation of methionine. Generally, our bodies use methionine to make something called s-adenosyl methionine (SAM) which is used for biosynthesis of hormones like dopamine and serotonin. (Deth, Cully) It breaks down into homocysteine which can be toxic at excess amounts but with the help of B6, B12 and folate it recycles back into methionine or glutathione. (This means we have to have substantial amounts of these nutrients too!) Methionine can also be used to make cysteine, cartinine, taurine and lecithin. Excess levels of homocysteine (homocysteinemia) has been demonstrated to have negative effects on the cardiovascular system, impair the urea cycle and may produce problematic cognitive effects. It has recently been demonstrated that PGC-1a effects homocysteine metabolism and overexpression of the antioxidant may elevate levels of homocysteine and lower PGC-1a expression is associated with lower plasma homocysteine levels. Low levels of homocysteine can alter the normal metabolism of glutathione, taurine and sulfate and therefore can be a health concern. Because homocysteine is the intermediate in the production of methionine to cysteine, it may make one more susceptible to oxidative stress and certain toxic exposures. In these cases, NAC, methionine and taurine are often recommended.

Now that we have reviewed how PGC-1a interacts with the methionine synthase pathway, let us now discuss more about this protein and its importance for maintaining overall cellular metabolism and homestasis. Homeostasis inside cells can be severely impaired without proper expression of PGC-1a because its expression influences the regulation of a number of other proteins including the PPARS, estrogen, thyroid hormone, glucocorticoids and the pregnane X receptor, just to name a few. (Finck) To demonstrate this take for example how the pregnane X receptor interacts with PGC-1a in the synthesis of CYPA26 and CYPA34. These are two enzymes necessary for the metabolism and/or detoxification of certain anesthetics, antidepressants, nicotine and other contaminants like certain molds. Additional key targets for PGC-1a include NRF1 and NRF2 which regulate mitochondrial function. The former, NRF1, is regulated by Nrf2 and taken together, Nrf2 and PGC-1a are responsible for most of the activities that promote oxidative stress resistance and cellular survival in toxic environments. PGC-1a also interacts with vitamin D and "because the expression of PGC-1α is regulated by environmental stimuli, such as diet and lower temperatures, it follows that the function of VDR could be influenced in response to these external stimuli in the tissues that exhibit an overlap in the expression of PGC-1α." (Savkur)

The PGC-1a gene responds to a number of different environmental cues including diet like fasting, caffeine, exercise and cold exposure and is preferentially expressed in tissues with high oxidative capacity. (Finck) On the other hand, it is inhibited by obesity, lack of exercise and the exposure to endotoxin. These factors lead one to consider important policy and regulatory concerns for the elderly and vulnerable populations, those with access issues to proper nutrition or individuals living with unhospitable conditions like contaminated water supplies. In general, the inhibition of PGC-1a expression has a variety of physiological effects including lower cardiac function, lower mitochondrial function, endothelial and epithelial dysfunction, poor thermoregulation, lower protection against environmental toxins, reduced energy metabolism, alterations of muscle fiber type and numerous others. One will note, all of these contribute to a variety of complications indentified in patients with environmental illnesses. As Patti describes, one complication from reduced PGC-1a expression leading to oxidative stress and altered cellular metabolism is insulin resistance and diabetes. As we noted earlier, PGC-1a interacts with NRF-1 a nuclear respiratory factor. This author demonstrates that although NRF-1 is reduced in diabetics, a number of other proteins that interact with and including PGC-1a such as PGC-1b, PPAR-gamma and NRF1 are also reduced in members of their families. From this it is assumed that decreased expression of PGC-1a is responsible for a decrease in NRF genes and the associated disturbances of insulin resistance and diabetes.

At this point, it would be worth suggesting here that metabolic disturbances may not only be the result of a reduction in expression in PGC-1a but may also be due to a reduction in the expression or regulation of NRF1 by Nrf2 at least in some cell types. One protein that has been implicated in a number of mental and physical health disorders, GSK-3b, is like an off and on switch for the Nrf2 antioxidant system that allows for cellular stress resistance. Also, other proteins may participate and PGC-1a inhibition. Tnf-a from cigarette smoke inhibites PGC-1a and may be a "key step" to vascular and myocyte dysfunction. (Tang) Both NRF1 and NRF2 are involved in the generation of the respiratory chain and it seems NRF1's role includes inducing gene expression and maintaining cytochrome C levels. An interesting article explains that several pathways exist that inhibit PGC-1a which may be different in different tissues. In addition to possible inhibition of PGC-1a in hepatocytes by Akt/PKB, there is evidence expression of PGC-1a can be dependant on reduction of a ligase called Cdc4 or through the activation of GSK-3b which also contributes to neuroinflammation. GSK-3b increases in response to oxidative stress and can regulate the TH1/Th2 balance (Ohtani) and its inhibition according to one author may lead to "stabilization of PGC-1a". Cdc4 is elevated in Parkinson's disease and as one author mentions, "it will be interesting to see if Cdc4 is responsible for the reduction of PGC-1a in the brains of PD patients." (Olson) For GSK-3b, metallothionein which can be upregulated by Nrf2 is an effective inhibitor of GSK-3b and prevents a number of diabetic-induced changes in inflammation, nitrosative stress and energy metabolism. (Wang) In cardiac cells the presense of metallothionein "abrogates mitochondrial damage, loss of mitochondrial DNA and downregulation of PGC-1a and its downstream targets. In this article the author proposes eNOS uncoupling induces the down-regulation of PGC-1a, NRF1, NRF2 and other proteins which contributes to the loss of mitochondrial biogenesis while saying further the precise mechanism for loss of mitochondrial biogenesis under eNOS uncoupling is not known. It might be important to stress here that it is now understood that Nrf2 is an important protective component against eNOS uncoupling. (Heiss) Recent evidence provides evidence of an alternative mechanism involving elevations in CO and H2O2 activates mitochondrial biogenesis through PGC-1a independantly of eNOS. In any event, PGC-1a expression is vital for normal heart function, because reductions in expression of PGC-1a results in compromised function. Other important inducers of PGC-1a include cAMP, CAMKII, AMPK and NO.

Numerous studies demonstrate and as we mentioned earlier, exercise elevates both PGC-1a gene and protein expression. As Wright explains, "with this discovery it was initially believed that exercise-induced biogenesis was mediated by increases in PGC-1a but suggests that activation of PGC-1a mediates mitochondrial biogenesis rather than the increases in protein expression." His study provides support for this because a) PGC-1a regulates binding of NRF1 and NRF2 and he demonstrates that their binding increased after exercise but before there was an increase in PGC-1a protein expression and b) a number of mitochondrial constituents were increased beforeelevations in protein levels. Other studies have demostrated that P38 activation is linked to an adaptive increase in mitochondrial biogenesis. Wright agrees and believes that generally PGC-1a production occurs in this order 1) exercise activates P38 which in turn activates PGC-1a 2) PGC-1a activates transciption factors and nuclear receptors that regulate mitochondrial expression which is part of the first phase of an adaptive response, 3) activation of the PGC-1a by the promoter and transcription factors coactivated by PGC-1a results in an increase in PGC-1a expression and 4) this mediates the second phase of an adaptive response and includes sustaining and enhancing mitochondrial biogenesis by PGC-1a. With all this in mind, one must consider that mitochondrial biogenesis and homostastic metabolism is dependant at least in part on participation of Nrf2 antioxidant system because it also regulates NRF1 and therefore, impairments of this system may contribute to conditions in metabolism where PGC-1a plays a central role.

Notes:

• Lipoic acid increases mitochondrial biogenesis and improves muscular energy through a AMPK-PGC-1a pathway which increases GLUT4 expression in aged mice. (Wang)

Original document and citations.

Mitochondrial Bioenergetics, CFS, Muscle Fatigue, PGC-1a, CAMKII and Nrf2.

Chronic fatigue syndrome is a condition that includes overwhelming fatigue even with rest that lasts for a period of six months or longer. It has been 3 decades since research on the condition began and there is no definitive answer on what causes it. However, they are making research strides and have an idea of at least some things that may contribute to it. SIRT1 activity regulates most of its activity through PGC-1a which an important regulator of metabolic homeotstasis, cellular function and mitochondrial biogenesis. Generally, cells that are lacking in PGC-1a are more insulin resistant and also have less eNOS.

In chronic fatigue syndrome, patients have a slow to fast twitch muscular presentation and altered muscle metabolism. (Pietrangelo) CAMKII is also important in fast-twitch muscle for sustaining contraction during exercise and it has been demonstrated that lower levels of CAMKII which are common in mitochondrial respiratory deficiencies may effect muscle performance. (Tanaka) AMPK is also another important regulator of this pathway through phosporylation of PGC-1a (Jager). AMPK also improves fatty acid metabolism in muscle and that activity is partially dependant on CAMKII (Rose). Again, a decrease in CAMKII would surely lead to changes in muscle metabolism. In this case, poor fatty acid metabolism causes higher fat in the muscle and is associated with insulin resistance and obesity and potentially, diabetes. (Adams) Interestingly, 89% of the muscles around the eyes and certain other areas of the face are fast-twitch muscles which may contribute to certain types of facial pain. Fast twitch muscle have less PGC-1a and as a result mitochondrial content is decreased and muscle activity is “energetically less efficient and expensive”(Schaffer). Cells with higher levels of PGC-1a have a better recovery of mitochondrial function to oxidant stress than those with lower levels of PGC-1a. (Rasbach) This would suggest a down-regulation or inhibition of SIRT1 activity which can be inhibited by many factors including nutrition including excessive calorie intake, Tnf-a or overproduction of H2O2. Many exposures including those to dioxin can increase levels of the pro-inflammatory Tnf-a (Frigo). Overall, cells with negative alterations in PGC-1a have demonstrated metabolic abnormalities, are more sensitive to cold, have more degenerative lesions and when expoxed to H2O2 are more apt to become damaged.

Because Nrf2 regulates NRF1 which is intricately tied and necessary for PGC-1a cellular function, Nrf2 becomes an important part of the pathway of SIRT1 and PGC-1a. Piantadosi describes the process as ”Nrf2 upregulates the mRNA, protein, and activity for HO-1 as well as mRNA and protein for nuclear respiratory factor (NRF)-1. Mechanistically, in cardiomyocytes, endogenous carbon monoxide (CO) generated by HO-1 overexpression stimulates superoxide dismutase-2 upregulation and mitochondrial H2O2 production, which activates Akt/PKB. Akt deactivates glycogen synthase kinase-3 (GSK3b), which permits Nrf2 nuclear translocation and occupancy of 4 antioxidant response elements (AREs) in the NRF-1 promoter.” (Piantadosi) In simple terms, GSK3b can become an on/off switch for Nrf2 and you got to have the promoter nuclear respiratory factor NRF-1 and Nrf2. In terms of mitochondrial function, it seems like the NRF-1/Nrf2 complex would be an important place where future therapies target. One already in existence that provides some of this action is metformin which is used as a diabetes treatment. Exercise may increase levels of PGC-1a but this is inhibited in insulin resistant muscle.(Filippis) Resveratrol and quercetin may improve mitochondrial function.


Notes:
****Nrf2 SNPS can be ethnically-derived which would make people with more (or less) susceptible to oxidative stress and possibly a decrease in mitochondrial biogenesis. (Marzec)
****SNPs or mutations may make Nrf2 less responsive or overly responsive to cell signals.
****Friedrich's Ataxia is a condition caused by an alteration in coding for Nrf2 which leads to poor induction of the antioxidant system. It is not the only form of ataxia. Read more about ataxia here. Other SNPs may cause one to be more sensitive to lung injury. Some of the symptoms may seem similar to those with some symptoms related to chemical sensitivity.

****The Nrf2 regulates a number of proteins including the aryl hydrocarbon which may be an important initiator and factor in multiple chemical sensitivity. The AhR is responsible for mediating the detoxification of PAHs and HAHs in addition to other xenobiotics. It has also been determined it mediates most of the toxicity associated with dioxins.


This is a list of common symptoms associated with CFS:
*cognitive dysfunction, including impaired memory or concentration
*postexertional malaise lasting more than 24 hours (exhaustion and increased symptoms) following physical or mental exercise
*unrefreshing sleep
*joint pain (without redness or swelling)
*persistent muscle pain
*headaches of a new type or severity
*tender cervical or axillary lymph nodes
*sore throat

Other Common Conditions:
*irritable bowel, abdominal pain, nausea, diarrhea or bloating
*chills and night sweats
*brain fog
*chest pain
*shortness of breath
*chronic cough
*visual disturbances (blurring, sensitivity to light, eye pain or dry eyes)
*allergies or sensitivities to foods, alcohol, odors, chemicals, medications or noise
*difficulty maintaining upright position (orthostatic instability, irregular heartbeat, dizziness, balance problems or fainting)
*psychological problems (depression, irritability, mood swings, anxiety, panic attacks)
*jaw pain
*weight loss or gain

Source: CDC

Citations: Original Post Source
****

Impairments in Muscle Function After Cigarette Exposure and Environmental Illness

PGC-1a a protein factor necessary for mitochondrial function and may be reduced with exposure to LPS as well as, from impairments in Nrf2. This study demonstrates that TNF-a (already identified as a factor in CFS and Parkinson's) is generated from exposure to cigarette smoke (and lots of other environmental contaminants) and has been shown to down-regulate PGC-1a that may lead to vascular and myocyte dysfunction. PGC-1a also regulates a number of glucose transporters such as GLUT1 and GLUT4 which trasport glucose into cells.  When one looks at a condition related to glucose uptake from impairment of glucose transporters such as in GLUT1 deficiency, there are recognizable patterns of impairment one may recognize in other environmental illnesses including CFS and fibromyalgia and also described as Parkinsonism and ataxia-like symptoms.  Because Nrf2 contributes to PGC-1a expression, a deficiency in Nrf2 may also present with these types of symptoms impaired after cigarette exposure and particulate matter from diesel exhaust. Of course, other factors such as accumulation of ammonia and genetic SNP may also pose potential cellular threats. PGC-1a can be increased through exercise but this will be dependant on the availabity of NRF1 (another protein) regulated by Nrf2/HO-1. Sauna and Waon therapy have been shown to elevate PGC-1a and Nrf2. Deficiencies of PGC-1a may exacerbate the autoimmune-type presentation of environmental illness in Nrf2 deficiencies which produce less HO-1. Lack of PGC-1a and Nrf2 may contribute to the development of chronic diabetes in addition to other metabolic complications and numerous other conditions, such as cardiovascular disease.


For review:

• Chemical Sensitivity and Th2 Autoimmune Disease: The Loss of Treg Cells As Referee!
• Immunosuppression in Environmental Illness By High Fat and Cytokines: Ameliorated By Green Tea Compound!?
• Nrf2 Expression Is Regulated by Epigenetic Mechanisms in Prostate Cancer
• T Regulatory Cells and Vitamin D - Their Importance to Environmental Illness Including Chemical Sensitivity.

CiteULike: TNF-alpha-mediated reduction in PGC-1alpha may impair skeletal muscle function after cigarette smoke exposure.: "Tang, K., Wagner, P. D., and Breen, E. C. (2010). Tnf-alpha-mediated reduction in pgc-1alpha may impair skeletal muscle function after cigarette smoke exposure. Journal of cellular physiology, 222(2):320-327."





Lihua CHE, N. and Chiwai WON, G. Estrogen-related receptor a inverse agonist enhances basal glucose uptake in myotubes through reactive oxygen species. Biological Pharmacology Bulletin, 32(7):1199-1203. http://www.citeulike.org/user/HEIRS/article/6512026
Arany, Z., Foo, S.-Y. Y., Ma, Y., Ruas, J. L., Bommi-Reddy, A., Girnun, G., Cooper, M., Laznik, D., Chinsomboon, J., Rangwala, S. M., Baek, K. H. H., Rosenzweig, A., and Spiegelman, B. M. (2008). Hif-independent regulation of vegf and angiogenesis by the transcriptional coactivator pgc-1alpha. Nature, 451(7181):1008-1012. http://www.citeulike.org/user/HEIRS/article/2406298
Pons, R., Collins, A., Rotstein, M., Engelstad, K., and De Vivo, D. C. (2009). The spectrum of movement disorders in glut-1 deficiency. Movement Disorders, 9999(9999):NA+. http://www.citeulike.org/user/HEIRS/article/6512017
Piantadosi, C. A., Carraway, M. S., Babiker, A., and Suliman, H. B. (2008). Heme oxygenase-1 regulates cardiac mitochondrial biogenesis via nrf2-mediated transcriptional control of nuclear respiratory factor-1. Circ Res, 103(11):1232-1240. http://www.citeulike.org/user/HEIRS/article/4617070?show_msg=already_posted
Glucose Transporter. Wipedia. Retrieved January 10, 2009.

PGC-1a , Cold, MCK, Myogenesis and Nrf2 and Environmental Illness?!

Background: Chronic fatigue syndrome has been shown in a study to have fast-twitch muscle fibers and cold sensitivity is a common complaint in patients with CFS. Mitochondrial biogenesis is dependant on a transcription protein that interacts with other proteins in mitochondrial synthesis. PGC-1a activity directly effects the number and density of mitochondria. Different tissues have different levels of mitochondria.
Other studies have shown that increasing the number of mitochondria may result in longer lifespan and improved quality of life. In mice, increasing the number of mitochondria can improve muscle weakness and increase survival.  With more mitochondria, mice lived longer without symptoms.

"The essential role of PGC-1 in adaptive thermogenesis is convincingly demonstrated by the observation that the PGC-1-deficient mice are unable to withstand a cold stress (4°C) for longer than 6 h due to a continuous decrease of core body temperature. Wild-type control mice, on the other hand, were able to tolerate the cold stress by keeping their core body temperature at 36.5°C, after an initial drop of 1.5°C.".....

Pietrangelo explains from his study that "fibre-type proportion was significantly altered in CSF samples, which showed a shift from the slow- to the fast-twitch phenotype. Lane showed several years ago that patients with lactate responses to exercise also exhibited a lower proportion of mitochondrial-rich fiber type. Liang explains that "skeletal muscle fibers are classified into three types: type I, type IIa, and type IIb. Slow-twitch type I and fast-twitch type IIa fibers contain more mitochondria and exhibit relatively higher rates of oxidative metabolism. In contrast, type IIb fibers have fewer mitochondria and are metabolically glycolytic. It is now well established that PGC-1 induces a remodeling of skeletal muscle fiber composition. In general, the ratio of glycolytic type IIb fibers to the more oxidative type I and type IIa fibers decreases. The expression of PGC-1 in skeletal muscle is readily inducible by both short-term exercise and endurance training in rodent models and human subjects. Our understanding of the biological role of PGC-1 in skeletal muscle structure and function has been greatly improved through the use of gain of function and loss of function mouse models. In a gain of function transgenic model, PGC-1 is overexpressed in a skeletal muscle-specific manner under the control of the muscle creatine kinase (MCK) promoter. PGC-1 overexpression results in the conversion of fast-twitch type IIb muscle fibers to type IIa and slow-twitch type I fibers by 20% and 10%, respectively, in plantaris muscle." Handchin explains the mice with an absence of PGC-1a in muscle present with an increase inflammatory cytokines including Tnf-a and IL-6 and that heterozygous animals produce smaller but significant increases in these cytokines. This provides evidence that inflammation, he says, is originating from the muscles themselves. A drop in PGC-1a expression in heterozygoes is similar to that of patients with a 36% drop in PGC-1a in diabetic patients which also corresponds to a PGC-1a drop in active vs. non-active animals. He says also that while one can not make a causality connection between PGC-1a and pro-inflammatory genes is not possible in humans, the patients do exhibit an increase in Tnf-a and Il-6 in muscle and Il-6 in serum. The reduction of PGC-1a mRNA in diabetic Type 2 patients is likely linked to a chronic state of low-grade inflammation." (Handchin)


Ding shows that "Nrf2 suppression blocks myogenesis. The knockdown of Nrf2 by siRNA transfection blocked the expression of myogenin and MHC, as well as morphological changes in myotube formation. We also verified these results via MCK-dependent luciferase assay using the MCK-responsive luciferase reporter plasmid, MCK-Luc. The knockdown of Nrf2 reduced MCK promoter activity, when measured 48 hours after the induction of differentiation." He also demonstrated that H2O2 signals are important for signaling and induction of GSH and the GSH/GSSH during muscle differentiation via Nrf2/GCL/GR/GSH signal pathway.



I can not provide all the citation below as it is in Japanese or Chinese.
Liang, H. and Ward, W. F. (2008). Pgc-1: a key regulator of energy metabolism. http://www.citeulike.org/user/HEIRS/article/5805611
Ding, Y., Choi, K. J., Kim, J. H., Han, X., Piao, Y., Jeong, J.-H., Choe, W., Kang, I., Ha, J., Forman, H. J., Lee, J., Yoon, K.-S., and Kim, S. S. (2008). Endogenous hydrogen peroxide regulates glutathione redox via nuclear factor erythroid 2-related factor 2 downstream of phosphatidylinositol 3-kinase during muscle differentiation. Am J Pathol, 172(6):1529-1541. http://www.citeulike.org/user/HEIRS/article/3481324
New Hope For Treating Common Form Of Inherited Neuromuscular Disease. Medical News Today.
Lane, R. J., Barrett, M. C., Woodrow, D., Moss, J., Fletcher, R., and Archard, L. C. (1998). Muscle fibre characteristics and lactate responses to exercise in chronic fatigue syndrome. Journal of neurology, neurosurgery, and psychiatry, 64(3):362-367. http://www.citeulike.org/user/HEIRS/article/3578915
Pietrangelo, T., Toniolo, L., Paoli, A., Fulle, S., Puglielli, C., Fan X00f2, G., and Reggiani, C. (2009). Functional characterization of muscle fibres from patients with chronic fatigue syndrome: case-control study. International journal of immunopathology and pharmacology, 22(2):427-436. http://www.citeulike.org/user/HEIRS/article/4812216
Handschin, C. and Spiegelman, B. M. (2008). The role of exercise and pgc1alpha in inflammation and chronic disease. Nature, 454(7203):463-469. http://www.citeulike.org/user/HEIRS/article/3038457

Nrf2 Regulation of Lipids and Glucose: Modulation of PGC-1a Through Protein

Over the past several months, I have proposed that certain environmental illnesses such as chemical sensitivity may be due to alterations in metabolic homeostasis from inflammatory processes and may include dysfunction of the antioxidant system Nrf2 and levels of PGC-1a, possibly through alterations in methylation or some other condition. Several recent studies provides a clearer picture of how this may occur in different tissues. PGC-1a is an important protein that participates in a number of processes including glucose and lipid regulation. (Kelly) In other blogs, we have explained how altered levels are apparent in the tissues of diabetes and for this reason, changes occur in metabolic function. As for Nrf2, it mitigates the effect of inflammatory cytokines as well as, upregulates proteins used in downstream processes of PGC-1a.

For several years now, it has been known that PGC-1a plays an important role in mitochondrial biogenesis and regulates cellular energy metabolism in the liver and muscle and is activated by SIRT1. SIRT1 is another protein we have discussed at length and is activated by the compound resveratrol in red wine and grape skins. Last year, one study showed that in neurons overexpression of SIRT1 or suppression of a GCN5 aminotransferase activated PGC-1a and increased mitochondrial density. Because, several experts have postulated that environmental illnesses may be due to mitochondrial dysfunction from exposures and endogenous processes, increasing mitochondrial density may reduce cellular impairment and increase neuronal survival and provide a therapeutic target.

It seems that GCN5 has the capacity to interact with the PGC family in general. Kelly et al recently found that GCN5 interacts with PGC-1b to repress its transcription activites associated with the estrogen receptor and NRF-1. As a result, the induction of GLUT4 and MCAD were reduced in skeletal muscle which translates to a blunted response of insulin-mediated glucose transport and increases the likelihood of the role of both PGC-1a and PGC-1b in metabolic disease.

As far as Nrf2 goes, in the liver the enzyme ATP citrate lyase (ACL)"relates energy balance" to GCN5 through the control of acetyl-CoA. In a new study by Kitteringham, the findings provide evidence that Nrf2 negatively regulates ATP citrate and therefore may provide a more influential role in glucose and lipid regulation than previously thought. (Kitteringham)

Notes:
***NO derived from constitutive nNOS plays a crucial role in the activity pattern of mitochondrial enzymes. In particular, the NO-mediated suppression of citrate synthase activity may be attributed to a regulatory function of NO in fatty acid synthesis. Inhibition of mitochondrial respiration by NO appears to be at least partially compensated for by a respective increase in the activity of respiratory chain complexes. (Schild) One could suggest the actions of Nrf2 may assist in the regulation of this function.



Kitteringham, N. R., Abdullah, A., Walsh, J., Randle, L., Jenkins, R. E., Sison, R., Goldring, C. E., Powell, H., Sanderson, C., Williams, S., Higgins, L., Yamamoto, M., Hayes, J., and Park, B. K. (2010). Proteomic analysis of nrf2 deficient transgenic mice reveals cellular defence and lipid metabolism as primary nrf2-dependent pathways in the liver. Journal of proteomics, 73(8):1612-1631.
http://www.citeulike.org/user/HEIRS/article/7329576

Jeninga, E. H., Schoonjans, K., and Auwerx, J. (2010). Reversible acetylation of pgc-1: connecting energy sensors and effectors to guarantee metabolic flexibility. Oncogene, aop(current).
http://www.citeulike.org/user/HEIRS/article/7282171

Wareski, P., Vaarmann, A., Choubey, V., Safiulina, D., Liiv, J., Kuum, M., and Kaasik, A. (2009). Pgc-1alpha and pgc-1beta regulate mitochondrial density in neurons. The Journal of biological chemistry, 284(32):21379-21385.
http://www.citeulike.org/user/HEIRS/article/4965303?show_msg=already_posted

Kelly, T. J., Lerin, C., Haas, W., Gygi, S. P., and Puigserver, P. (2009). Gcn5-mediated transcriptional control of the metabolic coactivator pgc-1beta through lysine acetylation. The Journal of biological chemistry, 284(30):19945-19952.
http://www.citeulike.org/user/HEIRS/article/5199678?show_msg=already_posted

Schild, L., Jaroscakova, I., Lendeckel, U., Wolf, G., and Keilhoff, G. (2006). Neuronal nitric oxide synthase controls enzyme activity pattern of mitochondria and lipid metabolism. FASEB J., 20(1):145-147.
http://www.citeulike.org/user/HEIRS/article/7329782

Possible roles of myostatin and pgc-1alpha in the increase of skeletal muscle and transformation of fiber type in cold-exposed chicks: expression of m

HEIRS Environmental Illness Research Blog: PGC-1a , Cold, MCK, Myogenesis and Nrf2 and Environmental Illness?!


HEIRS Environmental Illness Research Blog: PGC-1a , Cold, MCK, Myogenesis and Nrf2 and Environmental Illness?!

Title: Possible roles of myostatin and pgc-1alpha in the increase of skeletal muscle and transformation of fiber type in cold-exposed chicks: expression of myostatin and pgc-1alpha in chicks exposed to cold.

Summary: The author noted changes in bgoth myostatin and PGC-1a from cold exposure which the former was reversed upon removal from the cold environment. However, changes in PGC-1a were not seen 24 hrs after removal. These "results indicate that myostatin and PGC-1alpha expression in the skeletal muscle rapidly change in response to acute cold, suggesting the possibility that these two genes could be involved in the increase in muscle mass and transformation of fiber type, respectively, at the initial stage of adaptation in cold-exposed chicks."

Ijiri, D., Kanai, Y., and Hirabayashi, M. (2009). Possible roles of myostatin and pgc-1alpha in the increase of skeletal muscle and transformation of fiber type in cold-exposed chicks: expression of myostatin and pgc-1alpha in chicks exposed to cold. Domestic animal endocrinology, 37(1):12-22. http://bit.ly/muscle-fibers

Neuroinflammation,Diabetes and GSK-3b in Environmental Illnesses

Background: In other blogs, we have described how different proteins interact in molecular pathways to achieve specific metabolic processes. Most often we focus on the Nrf2-PGC-1a-SIRT1 pathway because activation or non-activation will effect cell survival. Recently, we spent quite a bit of time discussing the importance of PGC-1a for metabolic homeostasis and energy metabolism. Friedrich's ataxia is a neurodegenerative conditions that strikes early in life and have used FA as an example for comparison of complications of diseases that arise from Nrf2 dysfunction. Newer studies show that some of the complications in FA arise from dysregulation of PPAR-gamma and PGC-1a and symptoms associated with this dysfunction includes insulin resistance, cardiomyopathy and diabetes. Generally, dysregulation of the PPAR-gamma pathway which is anti-inflammatory leads to abherrant signaling from NF-kappaB. NF-kappaB increases mediation of inflammatory cytokines and in addition to inflammation and other health-related consequences, overexpression of NF-kappaB may alter drug metabolism including CYP3A4 which is responsible for the detoxification of over 50% of the drugs currently marketed.


Some of the most severe complications of environmental illnesses occur from neuroinflammation from inflammatory signals initiated through TLR and NF-kappaB. Under normal conditions, a number of different proteins interact to provide protective mechanisms to prevent inhibition of cellular function. It has been shown that GSK-3b overactivation is a major contributor to neuroinflammation through its role in the disruption of the blood brain barrier (Ramirez) and is at least in part, responsible for complications of a number of neurodegenerative diseases including PD. The activation of GSK-3 increases the production of a number of cytokines including IL-6 and inhibits IL-10. Both PPAR-gamma and another anti-inflammatory Il-10 that modulates sickness syndrome cytokines can inhibit GSK-3b. The over expression of the latter using a kind of "feedback mechanism". In addition to preventing neuroinflammation, GSK-3b inhibition also stabilizes PGC-1a and important regulator of normal mitochondrial biogenesis and energy metabolism. Other studies have showed that GSK-3b also inhibits glycogen synthase that regulates long term energy storage and may account for some of the weight problems reported in those with EI. This hormone is also inhibited by epinephrine and therefore, one may suggest that stress and overactive expression of GSK-3b may potentiate the effects of each other and further exacerbate complications of energy metabolism. In addition, this protein has been implicated as a factor contributing to a number of what are suspected to be neural inflammation-induced mental health conditions including autism, bipolar disorder, other mood disorders, Alzheimer's disease and others.  Incidentally, studies have demonstrated that both endotoxin may influence the activation of GSK-3b. Endotoxin has been implicated as a factor in environmental illness including chronic fatigue syndrome and it has been shown that endotoxin infection-induced GSK-3b by Tnf-a leads to a "synergistic effect" of increasing nitric oxide and reduction of IL-10 while promoting IL-6. GSK-3b, although a necessary protein, has potential for being a therapeutic target for a number of health conditions, including several that are under the "umbrella" of environmental illness. Several months ago we blogged about the evolutionary development of IGF-1 and its relationship to the olfactory system as well as DAF-16 and SKN-1 in lower organisms. Heavy metals may inhibit IGF-1 during the methionine cycle and is a common constituent of air pollution and particulate matter. Bondy explains how IGF-1 has an inhibitory effect on GSK-3b and has direct effects on neural growth and survival during brain development. She further explains how GSK-3b contributes to the loss of olfactory and dentate neurons when IGF-1 is underexpressed which may be important considering that environmental illnesses often present with loss of olfactory function and /or dysregulation.(Bondy) On the other hand , reductions in IGF-1 expression promote longer lifespans and reduce effects of endotoxemia while abherrant IGF-1 signaling may contribute to neuropathic pain, especially in diabetes. (Pabbidi) During nerve injury {ie lead (Williams), low-level toluene(Fujimata)}, NGF (Nicols) can activate both GSK-3b and nociceptors generating inflammatory pain.(Gould) Nociceptive behaviors have been implicated in MCS. (Pall)

Notes:

• EGCG, a compound in green tea, can suppress neurotoxicity by inhibiting GSK-3b.
• Exercise may positive influence the expression of glycogen synthase by inhibiting GSK-3b in skeletal muscle.
• Aging influences increased expression of GSK-3b. (Mercado-Gomez)

For Further Reading:

• GSK-3beta inhibition/beta-catenin stabilization in ventral midbrain precursors increases differentiation into dopamine neurons
• Promoters & Inhibitors of the Metabolic & Antioxidative Pathway of PGC-1a and Its Role in Environmental Illness

Original article and citations located here.

Dysfunction of Methylation and Nrf2 in Environmental Illness - Is This A Better Explanation than NO/ONOO- ?

One of the most important themes of my research is that accumulation of ammonia may play a causal role in including in conditions such MCS and autism through alterations in the methionine and glutamine synthetase pathway and elevations of ammonia in general which may change the expression of a variety of genes that regulate cell function. Of course, this has been suggested by a number of experts. Further, I also have proposed that the dysfunction in Nrf2 and related genes contribute to the severity and elicits autoimmune-type responses and chemicals such as PFOS may influence it or "trigger" it in addition to other chemicals that are more commonly considered as more toxic. In support, in support it has been suggested that hyperammonemia may alter that nitric-oxide-cGMP pathway (Hermenegildo) and as a result this could alter NO funtioning and contribute to conditions such as fibrosis in some tissuesand endothelial dysfunction. Alterations in the ornithine pathway may contribute to this but it is worth mentioning that NO may alter this pathway on it own. (Bauer) Interestingly, recently it has been reported that one of the benefits of fish oil may be mediated through the eNOS-cGMP pathway. (Lopez)  Nrf2 also has an important role in regulating NO and CO through its interaction with the antioxidant HO-1 and plays a substantial neuroprotective role against diseases such as Parkinson's disease. The deficiency or lack of Nrf2 expression offers one explanation of why individuals with MCS are so sensitive to carbon monoxide, nitrous oxide and other greenhouse gases. Mainly, because of the dysregulation of their regulator HO-1 by Nrf2. Tinnitus is common with MCS and can be associated with over-exposure to nitrous oxide which may also indicate problems associated with vitamin B and methylation. (Wipedia) Genetic polymorphisms in HO-1 and metal toxicity may also contribute to this problem. (You can see how lead, mercury and aluminum alter function in different steps in the cycle....here but you have to look closely.) Other Nrf2 interactions include modulation of Il-6 which is elevated in neuroinflammatory responses in the brain and Il-10 which is an anti-inflammatory that modulates sickness syndrome. According to a new report, sickness syndrome may be implicated in causing some of the symptoms of Gulf War Syndrome.


In addition, conditions such as elevations of ammonia activate the CRF pathway in animals that display hyperanxious behavior and recently this pathway has been shown to regulate both anxiety and depression as a consequence of stress. (Biomedicine) Interestingly, the glutamine pathway is also altered during depression and as a result, one may suggest this pathway may be dysregulated from exposure to chemicals such as PFOS and cause mood changes such as depression and anxiety and endogenous elevations of ammonia may induce mood changes even more. In addition, dysfunction of Nrf2 may lead to neurotoxicity and other consequences including augmenting ammonia accumulation. Chemical sensitivity has been implied as important in autism and ammonia may contribute to this which is produced endogenously and exogenously and many therapies used for MCS have also been used to reduce ammonia levels in autism. An interesting suggestion is that in some form through the dysfunction of Nrf2, deficits in the ornithine pathway contribute to the cellular toxicity experienced in MCS and autism. Of course, there are a number of other genetic defects that may alter the urea-cycle, including minor ones that may not appear until adulthood or later because of compensation from other pathways lost with ageing. Ammonia production is higher correlated with inflammatory markers in liver injury and has a profound effect on the permeability of the blood-brain-barrier, providing access of more toxic agents to brain tissue. (Jalan)

Alterations in the methionine pathway have also been suggested to play an important role in autism and we suggest here, MCS and relies on the notion of abherrant methylation "tagging" that potentiate the problems or vice versa. Q10 and vitamin B12 has been used as a therapy for MCS but is also used to assist mitochondrial function and support the methionine cycle and reduce ammonia, respectively. In methyl cycle disfunction, BH4 is drained in ammonia detoxification (Yasko ?) in addition in contrast to its role for NOS production and peroxynitrite which is part of the NO/ONOO- hypothesis. (Pall) Here we see the dichotomy between the Methyl Pathway and the NO/ONOO- hypothesis where BH4 is concerned. In one BH4-dependant process, NOS is converted to nitric oxide and on the other hand it assists in ammonia detoxification in the methylation cycle. If you put alterations in Nrf2 function, which is activated by ONOO- into the mix it can alter expression of genes important for these processes. ONOO- is not the only pro-oxidant that activates the Nrf2, it has been suggested that H2O2 is a much stronger activator and numerous other conditions normally upregulate Nrf2 in normal circumstances. Marzec recently demonstrated that SNPs that exist in the Nrf2 may make on more or less susceptible to oxidative stress and therefore cellular injury and disfunction. The inheritability hypothesis of epigenetics also relies on methylation and helps to explain why environmental illnesses largely run in families and the relationships between gene expression help to explain why gender plays an important role too! Unfortunately, alterations in methylation and consequently, alteration of function has been demonstrated in Nrf2 and several other genes implicated in environmental illness including autism. (To get an idea of how complicated genetics in environmental illness is --click here. ) In addition, alterations in Nrf2 and PGC-1a may contribute to diabetes and insulin resistance and are associated with POP exposures. In addition, GSK-3b involvement from reduced expression of PGC-1a, elevations in dopamine and exposures to bacteria (endotoxin) are a few additional factors that may hamper Nrf2 detoxification system which can lead to more elevations of neuroinflammatory processes, mood changes and significantly increase the likelihood of more neurodegeneration; all associated with environmental illness. GSK-3b signalling also may involve alterations in dopamine-regulated behaviors such as twitching (Tourette's) and ADHD that are often co-morbid with environmental illnesses after exposure injury. Incidentally, a number of behavioral responses to drugs (ie cocaine) can be reduced by GSK-3b inhibitors.

Currently, the NO/ONOO- cycle hypothesis which implicates elevation in ONOO as an important cause for responses in the conditions and proposed by Martin Pall, PhD is one of the most commonly accepted hypothesis to explain many of the symptoms in many environmental illnesses including MCS, chronic fatigue syndrome, fibromyalgia and PTSD. While this hypothesis is an important one, I can not say that it accurately describes the multi-inflammatory processes that occur in all of these illnesses and fails to adequately describe the metabolic processes that lead to these conditions. For one, obesity and insulin resistance and diabetes are important in environmental disease and the complications of ageing augment most of these and others as well. Recent evidence is highly suggestive these conditions may influence the development of the more commonly accept EI conditions and for this reason, I have to include them under that umbrella as well. In addition, there is no mention of methylation or how dysregulation of the antioxidant system Nrf2 negatively impacts the expression of NO, CO, HO-1, Il-10 as well as, modulates inflammatory cytokine expression. HO-1 (again with interaction from Nrf2) and vitamin D are involved in the suppressive function of regulatory Tcells. Their absence has been implicated in autoimmune disease that provides an explanation for why environmental illnesses like CFS and GWS and others including diabetes have autoimmune-type behavior. A recent study has presented the hypothesis that exposure to environmental pollutants and high ammonia levels directly alters Treg behavior. In would suggest the inability of oxidants including peroxynitrite and H2O2 to activate Nrf2 is one explanation for failure of the Nrf2 antioxidant system in addition to impairments in activation and regulation of Keap1 and genetic expression of the many genes that regulate the system in different ways. Not only does Nrf2 regulate NO but so does SIRT1 through AMPK, all of which are indirectly or directly involved in activating PGC-1a upregulated by exercise which prevents activation of GSK-3b that turns off the antioxidant system which provide upregulation of nuclear factors including NRF1. In further support, pharmaceutical therapies such as those that elevate PGC-1a and reduce ammonia levels, electroacupuncture, food therapies that elevate Nrf2 through sauna or Waon therapy and nutrition and antioxidant support to reduce mitochondrial dysfunction may be a valuable "tool kit" for the treatment of MCS, autism, provide some relief in CFS and PTSD and help prevent endothelial damage that may be instrumental in causing a number of conditions in many of them.

HEIRS Tags: ammonia, hyperammonemia, homocitrulline, diabetes, insulin resistance, GSK-3b, HO-1, Nrf2, PGC-1a, SIRT1, AMPK, NO/ONOO-, H2O2, dopamine, DAR, cocaine, encephelopathy, Il-6, neuropathy, B12, methionine


HEIRS Tags: ammonia, hyperammonemia, homocitrulline, diabetes, insulin resistance, GSK-3b, HO-1, Nrf2, PGC-1a, SIRT1, AMPK, NO/ONOO-, H2O2,

HEIRS H & H
**** Follow me on Twitter: HEIRS_Health
**** Read My Bio: HEIRS_Health

Original Article and Citations:

High Fat Diets Make One More Susceptible to Oxidative Stress and Environmental Illness!

Background:

• Obesity is also an important risk factor for a number of health conditions including diabetes and cardiovascular disease.
• Fatty liver disease is a condition where large amounts of fat accumulate in liver cells and is characteristic of metabolic syndrome. (Wipedia)

High fat diets decrease PGC-1a which is important for metabolic cellular processes, mitochondrial biogenesis and mitochondrial DNA synthesis. In addition, it decreases the expression of Nrf2 which is the master gene promoter that upregulates expression of genes important for the same process. The PGC-1a complex also controls another protein called Foxo3a which is an important modulator of aging. (Dong)

In addition to playing a role in redox homeostasis, Nrf2 modulates inflammatory mediators such as Tnf-a and MCP-1 and prevents lipid accumulation. Nrf2 is activated in response to toxicant injury and oxidative stress and is important for the detoxification of xenobiotics.
Tanaka's studies have shown the absence of Nrf2 increases susceptibility to toxicants including acetaminophen, hyperoxia, benzopyrene (found in smoke). He demonstrated that Nrf2 has important lipid metabolism and that feeding a high fat diet in the short term reduces Nrf2. He notes, other studies have shown long-term feeding of high fat diets increases Nrf2 and suggests this is an adapative response to oxidative stress induced by chronic fat accumulation. Generally, animals with lower Nrf2 present with elevated cholesterol levels and lower levels of Nrf2 results in the inability to prevent lipid accumulation, absence leads to greater retention of lipids in the liver (fatty liver disease) and greater oxidative stress including, oxidative stress in the mitochondria and the endoplasmic reticulum. Interestingly, Tanaka found that PGC-1a is reduced in high-fat diets but not in Nrf2 null mice which indicates the down-regulation of PGC-1a is dependant on Nrf2.

Summary: High fat diets reduce mitochondrial biogenesis, increases the likelihood for toxicant bioaccumulation and their overall toxic effects, increases oxidative stress, contributes to fat accumulation and obesity and impairs liver function which is an important organ for detoxification.

Dong, F., Li, Q., Sreejayan, N., Nunn, J. M., and Ren, J. (2007). Metallothionein prevents high-fat diet–induced cardiac contractile dysfunction role of peroxisome proliferator–activated receptor
coactivator 1 and mitochondrial biogenesis. 56(9):2201-2212. http://www.citeulike.org/user/HEIRS/article/5724999
Tanaka, Y., Aleksunes, L. M., Yeager, R. L., Gyamfi, M. A., Esterly, N., Guo, G. L., and Klaassen, C. D. (2008). Nf-e2-related factor 2 inhibits lipid accumulation and oxidative stress in mice fed a high-fat diet. J Pharmacol Exp Ther, 325(2):655-664. http://www.citeulike.org/user/HEIRS/article/4788030

Parkinson's and Link To Muscle Protein and Cell Signaling Pathway?

I recently noted that transcription factors such as MEF2, NRF1, NRF2 are co-activated by PGC-1a (important for mitochondrial biogenesis) results in kind of a loop to increase the expression of PGC-1a. PGC-1a regulates a number of transporters that regulate chemicals across membranes and alterations in these proteins may increase or lead to tissue dysfunction.

Recent evidence indicates that chaperone-mediated autophagy plays a role in direct degradation of neuronal transcription factor MEF2D, a protein known to promote neuronal survival. Disruption of this regulatory pathway by α-synuclein leads to neuronal stress, which may underlie neuronal loss in Parkinson’s disease.

For further reading:

• Nrf2's Regulation of NRF1 and Its Influence on NMDA Subunits and Environmental Illness
• Altered Metabolism, Toxicity, Glutamate Dehydrogenase and NRF-1 and Its Activator PGC-1
• Heme Oxygenase-1 Regulates Cardiac Mitochondrial Biogenesis via Nrf2-Mediated Transcriptional Control of Nuclear Respiratory Factor-1 -- Piantadosi et al. 103 (11): 1232 Figure IG7 -- Circulation Research
• Impairments in Muscle Function After Cigarette Exposure and Environmental Illness

Yang, Q. and Mao, Z. (2010). Dysregulation of autophagy and parkinson's disease: the mef2d link. Apoptosis. http://www.citeulike.org/user/HEIRS/article/6715832
Wright, D. C., Han, D.-H. H., Garcia-Roves, P. M., Geiger, P. C., Jones, T. E., and Holloszy, J. O. (2007). Exercise-induced mitochondrial biogenesis begins before the increase in muscle pgc-1alpha expression. The Journal of biological chemistry, 282(1):194-199. http://www.citeulike.org/user/HEIRS/article/6580001
Brockmann, K., Wang, D., Korenke, C. G., Von Moers, A., Ho, Y.-Y., Pascual, J. M., Kuang, K., Yang, H., Ma, L., Kranz-Eble, P., Fischbarg, J., Hanefeld, F., and De Vivo, D. C. (2001). Autosomal dominant glut-1 deficiency syndrome and familial epilepsy. Annals of Neurology, 50(4):476-485. http://www.citeulike.org/user/HEIRS/article/6715941
Hernandez, M. J., Roberts, T. M., and Hardin, C. D. (2007). Caveolin-1 and the organization of glycolysis in astrocytes: Modulation by ammonia. The FASEB Journal, 21. http://www.citeulike.org/user/HEIRS/article/6715979
Klinge, C. M. (2008). Estrogenic control of mitochondrial function and biogenesis. Journal of Cellular Biochemistry, 105(6):1342-1351. http://www.citeulike.org/user/HEIRS/article/3879108

Food Molds: Does Impairment of PGC-1a Contribute to Their Toxicity?

Background: PGC-1a is an important regulator of metabolism in different tissues including the muscle and liver and its expression may be of important significance in a variety of diseases including neurodegenerative diseases and diabetes and influences circadian rythyms.  In addition, its activities are directly influenced by a number of other proteins including AMPK and SIRT1.

Vomitoxin, also known as deoxynivalenol (DON) is a  mycotoxin found in different types of foodstuffs and can be associated with mycotoxicosis in both animals and humans.While its negative health effects are generally milder than other mycotoxins susceptible populations could be more at risk. Generally, this class of mycotoxins are proteins inhibitors and may alter expression of neurotransmitters such as serotonin which can lead to weight loss because of the anorexic effects of elevations of serotonin.  These changes may also influence normal activity of the respiratory tract. (Wipedia) According to a recent study and in-line with the DON's ability to negative influence protein expression, DON has been demonstrated to upregulate a known of repressor of PGC-1a in addition to other proteins.  This could explain why individuals ( or animals) with impaired antioxidant and immune systems, metabolic dysfunctions, or the aged may show more health effcts upon mold exposure. 


Osman, A. M., Pennings, J. L., Blokland, M., Peijnenburg, A., and van Loveren, H. (2010). Protein expression profiling of mouse thymoma cells upon exposure to the trichothecene deoxynivalenol (don): implications for its mechanism of action. Journal of immunotoxicology, 7(3):147-156. http://www.citeulike.org/user/HEIRS/article/7607619




Leone, T. C., Lehman, J. J., Finck, B. N., Schaeffer, P. J., Wende, A. R., Boudina, S., Courtois, M., Wozniak, D. F., Sambandam, N., Bernal-Mizrachi, C., Chen, Z., Holloszy, Medeiros, D. M., Schmidt, R. E., Saffitz, J. E., Abel, E. D., Semenkovich, C. F., and Kelly, D. P. (2005). Pgc-1α deficiency causes multi-system energy metabolic derangements: Muscle dysfunction, abnormal weight control and hepatic steatosis. PLoS Biol, 3(4):e101+.  http://www.citeulike.org/user/HEIRS/article/2909101?show_msg=already_posted

Altered Metabolism, Toxicity, Glutamate Dehydrogenase and NRF-1 and Its Activator PGC-1

Background: NRF-1 binding sites include ornithine decarboxylase and glutamate dehydrogenase through ADP Ribose in humans. Since NRF-1 associates with PGC-1a and Nrf2 -- I think one could suggest it elevates its importance in conditions possibly for those known to fall under the umbrella of environmental illness.

Definition:
****PFC: Perfluorinated compounds (PFCs) refer to a class of organofluorine compounds that have all hydrogens replaced with fluorine on a carbon chain—but also contain at least one different atom or functional group and persist as persistent organic compounds.
The two most studied PFCs are:
    **********PFOA or perfluorooctanoic acid, used to make fluoropolymers such as Teflon,   among other applications.
   **********PFOS or perfluorooctanesulfonic acid, used in the semiconductor industry, 3M's former Scotchgard formulation, and 3M's former fire-fighting foam mixture.


In a recent report, PFC from blood samples from loggerhead turtles were high enough that suggested liver damage and suppression of at least one immune function. (ScienceDaily: 2/22/08)

Quote for the day: I may not be a turtle but I am human....

I mentioned the article above because interestingly, I found articles related to similar chemicals found in  products in human home environments including our textiles, upholstery, carpets etc including perfluorooctanoic acid (PFOA) and similar to those found in turtles like those mentioned above. Chemicals such as these may influence the regulation of genes for amino acid metabolism...including those that overlap for methionine and glumate including GLUD1 (glutamate dehydrogenase in rats) and GLUL (glutamate ammonia ligase). "PFOA alters genes in wild-type mouse liver through PPAR alpha and a subset of genes are regulated by CAR and possibly PPAR gamma in the PPAR alpha-null mouse." As Corton explains, nuclear receptors can regulate nutrient and xenobiotic transport and metabolism and stress resistance and that "PGC-1 and PGC-1ß regulate the ligand-dependent and -independent activation of a large number of nuclear receptors including PPAR and constitutive activated receptor (CAR)." This would suggest that conditions that alter the expression of PGC-1a/PGC-1b may synergistically influence or oppose expression of these genes. From this one could propose these interactions may contribute to symptoms associated with environmental illness such as behavioral and mood changes or possibly even chemical sensitivity. These are chemicals that have been found in newborns and past studies show that PFOA cause tumors and are associated with developmental toxicity at high doses although admittedly, the health effects of these chemicals are mostly unknown.(ScienceDaily)


Rosso, L., Marques, A. C., Reichert, A. S., and Kaessmann, H. (2008). Mitochondrial targeting adaptation of the hominoid-specific glutamate dehydroge nase driven by positive darwinian selection. PLoS genetics, 4(8).
http://www.citeulike.org/user/HEIRS/article/3108334
MacMullen, C., Fang, J., Hsu, B. Y., Kelly, A., de Lonlay-Debeney, P., Saudubray, J. M., Ganguly, A., Smith, T. J., Stanley, C. A., and Hyperinsulinism/hyperammonemia Contributing Investigators (2001). Hyperinsulinism/hyperammonemia syndrome in children with regulatory mutations in the inhibitory guanosine triphosphate-binding domain of glutamate dehydrogenase. The Journal of clinical endocrinology and metabolism, 86(4):1782-1787. http://www.citeulike.org/user/HEIRS/article/6623806
Virbasius, C.-m. A., Virbasius, J. V., and Scarpulla, R. C. (1993). Nrf-1, an activator involved in nuclearmitochondrial interactions, utilizes a new dna-binding domain conserved in a family of developmental regulators. Genes & Development. http://www.citeulike.org/user/HEIRS/article/6623819
Hossain, M. B., Ji, P., Anish, R., Jacobson, R. H., and Takada, S. (2009). Poly(adp-ribose) polymerase 1 interacts with nuclear respiratory factor 1 (nrf-1) and plays a role in nrf-1 transcriptional regulation. Journal of Biological Chemistry, 284(13):8621-8632. http://www.citeulike.org/user/HEIRS/article/6623948
Haigis, M. C., Mostoslavsky, R., Haigis, K. M., Fahie, K., Christodoulou, D. C., Murphy, A. J., Valenzuela, D. M., Yancopoulos, G. D., Karow, M., Blander, G., Wolberger, C., Prolla, T. A., Weindruch, R., Alt, F. W., and Guarente, L. (2006). Sirt4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell, 126(5):941-954.  http://www.citeulike.org/user/HEIRS/article/6623971
Rosen, M.B., Lee, J.S., Ren, H., Vallanat, B., Liu, J., Waalkes, M.P., Abbott, B.D., Lau, C., and Corton, J.C. (2008). Toxicogenomic dissection of the perfluorooctanoic acid transcript profile in mouse liver: Evidence for the involvement of nuclear receptors pparalpha and car. Toxicol. Sci., 103(1):46-56. http://www.citeulike.org/user/HEIRS/article/6608986
Corton, J. C. and Brown-Borg, H. M. (2005). Peroxisome proliferator-activated receptor gamma coactivator 1 in caloric restriction and other models of longevity. J Gerontol A Biol Sci Med Sci, 60(12):1494-1509. http://www.citeulike.org/user/HEIRS/article/2339648?show_msg=already_posted

Nrf2, Ornithine Transferase, Autism and Maternal Age -- A Possible Link?

Recently a report was published of a link between autism and maternal age. While some may criticize that such admissions are worthless, I beg to differ. The Nrf2 antioxidant system which controls a battery of protective genes also controls an enzyme called ornithine aminotransferase which protects against ammonia. High ammonia levels have been implicated as a possible cause for some types of autism. There are behavioral conditions that may improve levels of Nrf2 expression including diet and exercise. While this may be premature, it should be worth more study from autism experts.

Past HEIRS Environmental Illness Research Blogs of Interest:

• Chronic hyperammonemia impairs the glutamate-nitric oxide-cyclic GMP pathway in cerebellar neurons in culture and in the rat in vivo.
• Mitochondrial MAO Enzyme May Contribute to Oxidative Stress in Hyperammonemia!
• Chronic hyperammonemia alters the circadian rhythms of corticosteroid hormone levels and of motor activity in rats.
• Episodic hyperammonemia in adult siblings with hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome.
• Hyperammonemia, Subordination, Hypoxia Influence Stress Hormone CRF Production in Fish
• Neutrophic Factors Protect Against High Ammonia Levels
• Ammonia, Methamphetamine, Cigarette Smoke and Parkinson's Disease
• Nrf2 and Cigarette Smoke ---A Possible Link to B12 Deficiency.......?
• Altered Metabolism, Toxicity, Glutamate Dehydrogenase and NRF-1 and Its Activator PGC-1
• Taurine rescues hippocampal long-term potentiation from ammonia-induced impairment.
• Effect of Acute Exposure to Ammonia on Glutamate Transport in Glial Cells Isolated From the Salamander Retina -- Mort et al. 86 (2): 836 -- Journal of Neurophysiology
• Endotoxin Inactivates Glutamine Synthetase and Impairs Ammonia Elimination in Rats
• Ammonia, ASIC Channels and Mental Health
• Ammonia and Its Relationship To Environmental Illness
• Appetite-suppressing effects of ammonia exposure in rainbow trout associated with regional and temporal activation of brain monoaminergic and CRF systems
• Effects of ammonia and allopurinol on rat hippocampal NMDA receptors.
• Elevated Ammonia and Endotoxin: Implications for Synergistic Toxicity in Environmental Illness
• ImmunoGenetics in Autism, MCS and Cancer -- What Has Food Got To Do With It!

HEIRS Library Tags: PGC-1a, Nrf2,
    Other Blog Tags: PGC-1a, Nrf2,

All HEIRS Posts are linked through Twitter:
Follow Us:


Thimmulappa, R. K., Mai, K. H., Srisuma, S., Kensler, T. W., Yamamoto, M., and Biswal, S. (2002). Identification of nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray. Cancer Res, 62(18):5196-5203. http://www.citeulike.org/user/HEIRS/article/3728059?show_msg=already_posted
University of California - Davis - Health System (2010, February 8). Link between advanced maternal age and autism confirmed. ScienceDaily. Retrieved February 9, 2010, from http://www.sciencedaily.com/releases/2010/02/100208102411.htm
Holmes, Amy, MD. Heavy Metal Detoxification and Metallothionein Promotion. Autism Treatments. The Healing Center Online. Retrieved on February 10, 2010.

PGC-1a methylation in abnormal weight newborns

Summary: "our findings suggest a potential role of promoter PPARGC1A methylation in metabolic programming....Another interesting finding was observed that large and small newborns for gestational age had a decreased amount of mitochondrial DNA.

HEIRS Citation: Pirola, C. Pgc-1a methylation in abnormal weight newborns.

For further reading

• More on PPARGC1A
• Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators.

Sauna Therapy Benefits Chemical Sensitivity By Altering Nutrient Toxicity!

Background: We have suggested over the past few months that multiple chemical sensitivity may result from an imbalance of metabolic processes the detoxify ammonia. This may be caused by overwhelming exposure from SIBO or genetic or environmental influences that inhibit the proper excretion of ammonia in urea. Several MCS experts, as well as patients, have found that dry sauna can be of benefit although thus far, there is no explanation of why this is so. In the past, we have written that sauna therapy is based on an ancient therapy called Waon therapy and past studies of this technique suggest it may increase the expression of Nrf2 and HO-1 and possibly influence the expression of PGC-1a. Both Nrf2 and PGC-1a have been implicated as having primary or secondary roles in mitochondrial biogenesis which of course, has benefits for health conditions where  mitochondrial respiration may be impaired. Also, Nrf2 has a role in neuroprotection and may modulate the ornithine pathway which is protective against ammonia toxicity.

A recent study has demonstrated that sauna/sweat therapy may lead to the reduction of nicotinamide. Nicotinamide overload has recently been implicated as a factor in causing insulin resistance, oxidative stress by H2O2 and possibly type 2 diabetes and other studies have shown that pollution may influence the development of this disease.  Other findings show skin damage and certain chemicals may reduce nicotinamide excretion. In general, nicotinamide is generally considered anti-inflammatory but at higher doses may be toxic to the liver. Nicotinamides are active inhibitors of SIRT proteins which are not only important for a number of metabolic processes but they also play a role mitochondrial biogenesis. On the other hand, higher ammonia levels can inhibit the TCA cycle which are a major producer of nicotinamides. Taking these conditions into account, we see a potential for sauna (via sweat therapy) to positively reduce the  production of toxic levels of nicotinamides while reducing ammonia toxicity through elevations in Nrf2 and the ornithine pathway.   The reduction of MCS symptoms could be a consequence of one or the other or both...!

For further reading:

• SIRT1, Nrf2 and Saunas -- September 6, 2009

Zhou, S.-S. S., Li, D., Sun, W.-P. P., Guo, M., Lun, Y.-Z. Z., Zhou, Y.-M. M., Xiao, F.-C. C., Jing, L.-X. X., Sun, S.-X. X., Zhang, L.-B. B., Luo, N., Bian, F.-N. N., Zou, W., Dong, L.-B. B., Zhao, Z.-G. G., Li, S.-F. F., Gong, X.-J. J., Yu, Z.-G. G., Sun, C.-B. B., Zheng, C.-L. L., Jiang, D.-J. J., and Li, Z.-N. N. (2009). Nicotinamide overload may play a role in the development of type 2 diabetes. World journal of gastroenterology : WJG, 15(45):5674-5684. http://www.citeulike.org/user/HEIRS/article/6885712
Whitaker, M. J. and Steinhardt, R. A. (1981). The relation between the increase in reduced nicotinamide nucleotides and the initiation of dna synthesis in sea urchin eggs. 25(1):95-103. http://www.citeulike.org/user/HEIRS/article/6885757
Smith, D., Wang, T., Španěl, P., and Bloor, R. (2006). The increase of breath ammonia induced by niacin ingestion quantified by selected ion flow tube mass spectrometry. Physiological Measurement, 27(6). http://www.citeulike.org/user/HEIRS/article/6885842
Katunuma, N., Okada, M., and Nish, Y. (1966). Regulation of the urea cycle and tca cycle by ammonia. Advances in Enzyme Regulation, 4:317-335. http://www.citeulike.org/user/HEIRS/article/6885732

Nitrosamines and PGC-1a

PGC-1a is an important component for the detoxification of nitrosamines. Excess levels can lead to enhanced toxicity. A recent study shows nitrosamine increases oxidative and nitrosative stress and elevates inflammatory mediators including Tnf-a , MCP-1 and Il-1 by activation of microglia and astrocytes resulting in neuronal damage. Nitrosamines are chemical compounds which are produced from nitrites and secondary amines. Some are carcinogenic are can be produced from certain methods of cooking and are also in beer and latex. (Wipedia)




Ghosh, D., Mishra, M. K. K., Das, S., Kaushik, D. K. K., and Basu, A. (2009). Tobacco carcinogen induces microglial activation and subsequent neuronal damage. Journal of neurochemistry, 110(3):1070-1081. http://www.citeulike.org/user/HEIRS/article/5202108
Nitrosamines. Wipedia. Retrieved on September 6, 2009.

SIRT1, PGC-1a and Exercise

Dumke et al demonstrated that successive bouts of exercise in normal already trained subjects increases expression of cytochrome c, citrate synthase, PGC-1a and SIRT1. This is the first study that shows an increase of SIRT1 with acute and chronic exercise.


Dumke, C. L., Mark Davis, J., Angela Murphy, E., Nieman, D. C., Carmichael, M. D., Quindry, J. C., Travis Triplett, N., Utter, A. C., Gross Gowin, S. J., Henson, D. A., McAnulty, S. R., and McAnulty, L. S. (2009). Successive bouts of cycling stimulates genes associated with mitochondrial biogenesis. European journal of applied physiology. http://www.citeulike.org/user/HEIRS/article/5415657

Saturated Fats, High-fat Diets and Coconut Oil -- No, There NOT that Good For You

The Real Facts About Coconut Oil --

If You HAVE Environmental Illness It May Not Be Good For You

There seems to be some misunderstanding about fats in general and environmental illness, so I thought I would provide some information to you and as a reader, if you have environmental illness of one sort or another the information in the paragraphs below pertain specifically to you.  First of all, part of the consequences of injury from environmental illness includes insulin resistance, damage from inflammation and endothelial dysfunction (Helyar) due to bioaccumulation and the chemicals effects on cellular function and signaling. Almost everyone in the US and Canada...in cities or the country that do not grow all their own food on organic farms have some levels of toxins stored in their body and the fat cells are most often, where they are stored. Arsenescu explains how dioxins and PCB both have been shown to increase and expand adipose tissue and therefore, there is significant potential for toxic exposures that lead to obesity, cardiovascular disease, diabetes and cancer (Rutkowski).  Yoshanari explains that the effects of toxins are still unclear but there is mounting evidence that toxicants can change the function/secretion of adipokines produced by adipocytes and have important roles in metabolic and endocine function. His research suggests that lipophilic toxicants in adipose tissue "activate the aryl hydrocarbon and the Nrf2 which increase detoxification but also may change the genetic expression of adipokines resulting in unexpected effect on tissue." Interestingly, animals that are AhR-/- do not gain weight in response to dioxin which suggest suppression of expression. (Arsenescu) Abdollahi and Rezg demonstrates subchronic effects of malathion exposure upsets glucose homeostasis and may induce diabetes through mechanisms including increased energy needed for detoxification and a decrease in paraxonase activity. Incidentally, Rezg's findings also show  some of the harmful effects of malathion can be aleviated with the addition of the polyphenol caffeic acid which increases acetylcholinesterase.

To some extent the effects of a high-fat diet, atleast in terms of changing gene expression, parallel those of the effects of toxic injury on adipocytes and both exacerbate the impact of each other. A "sedentary lifestyle and overeating are two conditions that are associated with weight gain and obesity that lead to insulin resistance. Insulin resistance is a condition where insulin has less than desired effects of disposal of glucose in the muscle and the improper suppression of glucose production in the liver.  Obesity and mitochondrial dysfunction are risk factors for insulin resistance and obese individuals have smaller mitochondria and exhibit compromised mitochondrial bioenergetic capacity. Insulin resistance also occurs with age, and a related defect in fatty acid oxidation has been identified." (Liang) Several conditions can influence the development of insulin resistance and sedentary lifestyles and overeating can be characteristic patterns of behavior of those who are ill. Researchers suspect there are a number of physiological consequences of bioaccumulation including the increase of inflammatory mediators that can lead to insulin resistance, for example, through increases in Tnf-a. Certain fats including those in coconut oil, like Tnf-a, can switch off important genes necessary for cellular metabolism including PGC-1a which may lead to a gradual shut-down of the mitochondria. Environmental influences like these may also explain the development of diabetes in adulthood. (Coghlan) Exercise, sedentary lifestyles and nutritional factors have all been demonstrated to regulate PGC-1a and regulate insulin sensitivity. Inflammation in the "fat" can also leak out and cause inflammation in the muscles surrounding them increasing insulin resistance.

Below is some general information related to fat which is important because insulin resistance is a risk factor for diabetes and diabetes is associated with bioaccumulation and obesity and environmental illness. One needs to understand the concept of triglycerides in addition to fat. Corcoran explains that "intracellular triglycerides are associated with diminished insulin sensitivity in skeletal muscle. This lipid accumulation is likely due to enhanced fatty acid uptake in the muscle coupled with diminished mitochondrial lipid oxidation. Excess fatty acids are esterified and either stored or metabolized to various molecules that may participate or interfere with normal cell signaling, particularly with insulin, mediated signal transduction and subsequently whole body glucose metabolism. Impaired insulin responsiveness if not managed, can lead to diabetes.  Chronic over-consumption of calories coupled with deleterious intakes of fats have been shown to increase the risk of insulin resistance." These statements become particularly important to those with chemical injury and environmental illness because inefficient mitochondria and inflammation makes the body more insulin resistant. Most of the studies already published on the health benefits of fats in coconut oil,as far as I can tell, are on healthy people that do not have chemical sensitivities and do not have uncontrolled oxidative stress and do not have diminished mitochondrial function and insulin resistance already present.

Here are some important facts and definitions to understand when it comes to fat: American Diabetes Association

The ADA recommends less than 7% of saturated fat per day for most people. The exact amounts truly depend on a variety of factors including age, physical activity etc. Most Americans get more than that and I would assume so do most Canadians.

• 
  
  
  Generally, saturated fat raises cholesterol. From what I can see from the research, there is not a lot of evidence of coconut doing so directly, even though the ADA says it might. Saturated fat is in meats, lard, butter etc. Palm, Palm Kernel and Coconut oil are saturated vegetable oils. The have a different molecular formula from traditional longer-chain hydrogenated fats and are made of medium chain fatty acids. Trans fat is what is called hydrogenated oils and we know them as the oils that are more solid and found in snack food that are labelled as such, stick margarine, shortening and fast food.
  
  
  
• 
  
  
  Monounsaturated fats are those that are the more healthy fats and are sometimes called seed oils and may include canola, avocado, etc.
  
  
  
• 
  
  
  Polyunsaturated fats include corn oil, sunflower oil, cottonseed oil, etc.
  
  
  
• 
  
  
  Omega - 3 -- in fish and some plants, ie flax.
  
  
  
• 
  
  
  Cholesterol -- you body makes it and it comes from your diet.
  
  
  

Note: Coconut oil does not provide a good source of essential fatty acids so it is not a good replacement for sources that do. (Hargrave)

You may have noted some of the recent positive reports that have been published in the media lately not just about coconut oil but also medium chain fatty acids. The first one is they may help prevent diabetes better than long-chained fatty acids. Yes, this may be true if the results of the study are correct. However, this is not the full story. When doing health research or presenting health information to people that are already ill, one needs to dig a little deeper. Lets take a look at the fatty acid profile of coconut oil. By the way, I looked at the label on jars I bought --90% or more of the fat in coconut oil is saturated fat. It does not matter if you buy organic, virgin or extra-virgin coconut oil most of the fat in coconut oil is saturated fat. Also, in case your interested according to most of what I read there is little or no difference in virgin or extra-virgin coconut oil. It is labelled like this to be more marketably friendly so it can more favorably compared to olive oils. Virgin coconut oil is regarded as the highest quality coconut oil and is preferred for food preparation and home medicinal use. 18 members of Asian and Pacific Coconut Community (APCC) make about 85% of the coconut oil produced. (Wipedia)

The Natural Medicine Comprehensive Database has determined there is insufficient evidence that coconut oil can be used effectively to treat the flu, candida, the common cold, HIV/AIDS, preventing maternal HIV transmission, gonorrhea, candida infections, etc. and the safety for use as a medicinal is not known. George Mateljan is an expert on alternative nutrition and started one of the largest organic health food companies in this country. He has written several books about nutrition and his last book, the World's Healthiest Foodsis almost 900 pages and full of well-researched information. It was published in 2007 and even now is considered somewhat outdated because of the advances in research in the study of lipomics. If you want a good resource about nutrition and how to cook good food, it is definitely worth a gander and if you like, a purchase. This is what he writes about coconut oil. "Coconut oil is mostly saturated fat and as it turns out, not all saturated fat is bad for you. Of the saturated fat found in coconut oil, only 9% is made of long-chained fatty acid which are associated with heart disease. (This may be true but there are lots of other health conditions that can be exacerbated by fat!) Most of the fat in coconut oil is lauric acid which has a reputation of being heart-healthy. (Yes, but as you will see, may not be good for MCSers) About 30% of the medium-chain triglycerides can be taken up from the digestive tract and into the blood without metabolic work. Since coconut oil is mostly medium-chain triglycerides it can provide the same benefit. (I would expect if a person has some types of intestinal dysfunction, it could cause diarrhea or a similar malady. It might be beneficial to ask a physician about this!)

I (meaning Mr. Mateljan) have noticed that coconut oil is well promoted on the Internet with many claims for its health benefits. Mostly notably for its antiviral activity. But from the research I have seen, most of the conclusions are preliminary given there is not that much research published on the subject and that is done mostly on the individual components. But it looks pretty good for coconut oil but I (meaning he) will look at the research as it comes in." This is his opinion and again, I have to say that at the time it was published this may have been true. However, there are numerous discoveries on lipid regulation that have been made that he may not have been aware of or are newer than when the book was published and/or written. Also, I am sure he does not research with a perspective of someone with environmental illness because he is a chef, entrepreneur and a nutritionist. The statements in his book are also published on his website and as far as I can tell from what I read, what the website says and what my book says is no different. Again, the name of the book is the World's Healthiest Foods by George Mateljan.

Garvan notes a typical Western diet contains 40% saturated fat, 40% monounsaturated fat, 20% polyunsaturated fat of which most are omega-6 not omega-3. Thus high-saturated fat diets are contributory to diabetes and obesity.  In addition, because there are no essential fatty acids in coconut oil, a diet in saturated fat usually is essential fatty acid deficient in linoleic acid an omega-6 fatty acid and alpha-linolenic, an omega-3 fatty acid. (Best)

This is the FA Profile of Coconut Oil: Wipedia

Fatty Acid	Saturation	Carbons	Percent
Caproic	Saturated	6	0.5
Caprylic	Saturated	8	7.8
Capric	Saturated	10	6.7
Lauric	Saturated	12	47.5
Myristic	Saturated	14	18.1
Palmitic	Saturated	16	8.8
Stearic	Saturated	18	2.6
Arachidic	Saturated	20	0.1
Oleic	Monounsaturated	18	6.2
Linoleic	Polyunaturated	18	1.6
Coconut oil contains approximately 92.1% saturated fatty acids, 6.2% monounsaturated fatty acids, 1.6% polyunsaturated fatty acids. The above numbers are averages based on samples taken. Numbers can vary slightly depending on age of the coconut, growing conditions, and variety.

As you can see from the table above, the most of what is contained in coconut oil is lauric acid, myristic and palmitic saturated fats. First, let me draw your attention to lauric acid. The amount of lauric acid in coconut oil is 47.5% according to the chart above. 3dChem.com describes lauric acid as the main oil in palm oil and coconut oil and that it has antimicrobial properties. It also says that lauric acid is slightly irritating to mucous membranes and is used in soaps and shampoos. Sodium lauryl sulfate is the most common lauric-acid derived compound used for this purpose. Yes, SLS is used in food and several different types of food from regular table food to pharmaceuticals. Lauric acid can react with solvents like water, as well as fats, which is why SLS is used in shampoo. As most people already know many MCSers are very sensitive to SLS. Other studies have shown that it can cause sensitivities in people that take medication made with SLS. In skin, SLS has been demonstrated to inhibit lipid-metabolizing enzymes including PPAR-alpha and PPAR-gamma which if you have read my blog can already be down-regulated by Tnf-a. (Torma) Tnf-a can be produced as a consequence of the stress response and toxic injury and therefore may be quite prevalent in environmental health conditions. One of the functions of PPAR-gamma includes regulating insulin sensitivity (Chatterjee) which is mediated by adiponectin that reduces insulin resistance. Adiponectin also is down-regulated by Tnf-a and has been shown in a study to be down-regulated by the high-fat of coconut oil (Bueno). Another study shows, SLS mediates skin barrier injury after 5-weeks and makes it more sensitivity to external stress. Considering that lauric acid is an irritant and is found in SLS....one can assume that it may be the agent at least in part that causes the irritation from SLS in people who are already sensitive to different "agents". Another study shows ceramides are also increased by SLS and ceramides from mitochondrial dysfunction down-regulate Nrf2 so one may be able to make a connection with further information and research. Nrf2 can be impaired for a number of reasons including age and genetics and makes one more susceptible to oxidative stress and susceptible to aberrant inflammation. It is also down-regulated by hyperglycemia (high blood sugar) and high-fat diets. Now, there is no specific research that says that lauric acid is the only thing in SLS as far as I can tell that may be an irritant, but the fact that it is in there and if a person is sensitive or thinks they may be sensitive to SLS, it might be a good idea to stay away from it. Not all MCSers are sensitive to SLS, but I am one and therefore, no matter how useful it is for cooking, I would never think about using it. I would rather be safe now than sorry later because my reactions can occur quickly or be delayed by hours or even days.

Many studies note that medium-chained fatty acid do not result in the accumulation of fat in muscle and the liver and from all accounts medium-chained fatty acids are better healthwise than long ones. But there are a few things one must consider since the American diet consists of 40% saturated fat which is 33% more than is recommended. In the literature, there seems to be some debate about the effect of long-chained fatty acids on mitochondrial function. Schrauwen says they have little effect and others say they may impair mitochondrial function by example, by opening of the transition pore that increases mitochondrial swelling causing cell death. (Wiekowski, Korge) As noted above, a recent claim was made that short-chain FA can prevent diabetes. (Medical News Today) Well, in actuality the study says it can preserve insulin action in muscle and adipose tissue. Which is great if you have healthy adipose tissue and muscle --and as we have shown people with environmental illness probably do not! In addition, it says that it does increase steatosis (fatty liver) and insulin resistance in the liver and there are alot of mitochondria in liver cells. (Turner) Many people that have been exposed to toxicants have injured livers in addition to impaired functioning of the mitochondria. Personally, I really do not want my liver fatty because it has to last a really long time...well, hopefully anyway! Most people are uneffected by fatty liver but then there are others where the condition results in elevated inflammation and scarring and at its worst, liver failure. (Mayon Clinic) If one reads that coconut oil gives an energy boost the author may be extrapolating from the fact that fats provide energy which I have to argue at least to a point. It may be true but it may not be true in people with mitochondrial disease or dysfunction. Garvan explains a benefit of medium-chain fatty acids is they are small enough to cross the membrane and supply energy to the mitochondria. That is all fine and good if the mitochondria are working well but alot of excess energy is not so good if they aren't. Mitochondrial function naturally generates free radicals and an increase in them may generate an increase in oxidative stress that may impair it further and may induce other aberrant signaling the least of which may include drastic changes in mood. There is evidence the activity of PKC is "defective" in diabetes and obesity and as a result may lead to altered glucose transport. (Corcoran) New research has implicated PKC signaling in fatty-acid induced insulin resistance and others identify PKC involvement in connection with lead poisoning and PTSD although I have yet to follow up on the specifics. Many people including those with environmental illness have stored levels of lead and other metals that are released under physiological stress conditions. Many conditions including exposures may result in a hyperglycemia response, so alterations in PKC signaling is something one must consider. You might recall a recent report showed a higher incidence of metabolic syndrome in those with PTSD. PKC signaling may offer a possible explanation and then again, maybe it doesn't.

Palmitic acid is also known as palmitate which is the salts or esters of palmitic acid. (Wipedia) It is one of the most common fatty acids in plants and animals and is number 3 on the list of fatty acids in coconut oil. It too shows no hypercholesterolemic effects from what I initially saw from the research. But that does not mean it can not in certain people or that it does...it just means I did not find it. Except and this is a big except, in the presence of trans fat which unfortunately, is still a big part of many people's diet even though many try to avoid it.   Eli Lilly produced a report that indicates that palmitate causes down-regulation of PGC-1a which is an important requirement for mitochondrial biogenesis which the end result is energy. It is safe to assume that down-regulating PGC-1a can be more detrimental to cells that already have less mitochondria that function abnormally and are insulin resistant. (Otto) eNOS can also be deficient in PGC-1a deficient cells which may increase the risk for endothelial dysfunction that has been implicated as a factor in a number of environmental illnesses.  Bonnard's studies suggest that high-fat, high-sugar diets can induce glucose intolerance after 1 month and a longer intervention with the same diet induced diabetes with altered mitochondrial biogenesis, structure and function and concludes that insulin resistance precedes mitochondrial dysfunction in diet-induced diabetes. (Bonnard)  Schrauen explains that palmitate, myristate and stearate do activate the NF-kappaB in muscle cells and since if one refers back to the chart above those three acids equals almost 30% of the saturated fat in cocnut oil. NF-kappaB may activate inflammatory processes which some called the "inflammatory cascade" and is implicated as an inflammatory marker in environmental illness. In people with lower Nrf2, NF-kappaB is a concern because Nrf2 normally is responsible for regulating it.

A just released paper indicates that palmitic acid changes brain chemistry in a "relatively short time" and tricks the brain into not realizing when one is full from eating. It does this by making the brain unresponsive to signals from leptin and insulin and therefore may cause one to overeat. (US News) This may contribute to the "expanding adipose tissue" problem and more inflammation we mentioned in the first paragraph. Now, granted palmitic acid makes up only 8% of the total fat content. If your like me, I do not want to be exposed to anything that changes my brain chemistry anymore that it has been already. At least that is, if I can avoid it. I have enough problems with sickness syndrome and brain fog! Palmitic acid has been demonstrated to cause a 75% increase in the expression of Tnf-a and a 75% decrease in Il-10 in adipocytes and Tnf-a is associated with environmental illness and causes insulin resistance and inhibits PGC-1a in vitro cardiac cells. (Palomer) (The increase in Tnf-a may explain some of the weight loss seen in some studies considering that Tnf-a causes cachexia and weight loss. Il-10 is associated with preventing lipid-induced insulin resistance, reducing the severity and length of sickness syndrome and modulating HO-1. All of these factors have been implicated as possible factors in environmental illness. (Bradley) Yamauchi shows that insulin resistance in lipoatrophy can be reversed with expression of both adiponectin and leptin but only partially by either leptin or adiponectin alone. (Yamauchi) In other words, there may be instances that if one or the other of these genes are down-regulated then they may not be able to reverse insulin resistance if already present. Generally, high-fat diets are associated with impaired working memory and hippocampal morphology in animals. (Granholm)

Two important notes about the issues above, one needs to be careful when drawing conclusions about the health aspects of a population in comparison to another. If one population does not eat like another, live like another, work and exercise like another, have the same cultural problems, the same genes, and in this case, share the same disease or health condition it may lead a person to make conclusions that are inaccurate. Most indiginous populations, especially those isolated by geography are not effected by the same environmental influences modern societies are and therefore the aspects of their environmentally-related health conditions are different. I have read what is printed on "more popular" websites and also have read cultural graduate theses and there is some contradiction of the health effects of medium chain high-fat diets in different indiginous population studies. I am not saying comparison studies are not important but the more similar the cultures are the more valuable the data. Here are are few important things one might consider in a population study on fat. Are there other factors such as there are in this case, in the diet or lifestyle that may be offsetting the negative effects of a high-fat diet? Have their bodies adapted to their circumstances over time better than other populations? A recent study has demonstrated that the anti-inflammatory effects of vitamin E may be associated with certain Tnf-a and it has been suggested that the positive benefits of coconut oil are that it is a good source of vitamin E.  Could up-regulated or down-regulated genes be altering the expression of proteins or is there a gene polymorphisms in the population being studied that makes them more adaptable to handle a negative influence? Are there comfounding factors that are increasing the health or inhibiting the effects such as more or lack of exercise or the use or no use of trans fat? As you can see from what was written above about the studies from palmitic acid in junk food and coconut oil down-regulating adiponectin, food can change the expression of genes quite quickly and researchers have no idea how long the effects can last. Is it possible these changes can become permanent on a population that has not fully "adapted" to them.  Maybe, maybe not. It would be my guess no one will say it can not happen because no one really knows for sure. There is now a whole field of research that explores how changes in gene expression is passed down to the next generation when there is no change in the DNA. Twenty years ago, researchers did not believe epigenetic influences could happen either.  

Environmental illness development is largely due to poor (I use this term loosely) diet, lifestyle, and exposures to toxic influences like chemicals and their influence on genetic expression and numerous other factors including bad decisions and choices.  In addition, scientists  are well aware toxicants can can up-regulate or down-regulate cellular receptors or interact with each differently and may lead to altered cell functions. There are thousands of chemicals now on the market that have the potential to do it. From a political and policy-making standpoint, the problem is how one goes about deciding which ones to to start testing first, who is gonna test them and what standards will be used to test them and also, who is gonna pay for it and how to deal with the economic fall-out afterward! Finally, making health decisions is in the end, a personal one and it is only that person, or mostly so, who has to live or not live with the consequences. Using coconut oil for cooking is still of benefit for one person because it does not produce the levels of aldehydes and does not turn rancid like other oils. But it may not be a wise choice for another who has a sensitivity to it or one of the chemicals in it. On the other hand, detoxification of aldehydes is often limited in environmental illness and therefore, cooking with coconut may be a better option for someone with one environmental illness compared to another person with another environmental illness.On the other hand, in many cases because of the nature of injury and inflammation in environmental illness, limiting fat should be of benefit to most. Unless of course, medical tests show a deficiency. Either way there are good lab tests available that can determine a person's fat and triglyceride status and a physician is more than qualified to discuss the topic.

 

 

 

 

 

Sonne, C., Fonfara, S., Dietz, R., Kirkegaard, M., Letcher, R., Shahmiri, S., Andersen, S., and Møller, P. (2007). Multiple cytokine and acute-phase protein gene transcription in west greenland sledge dogs (canis familiaris) dietary exposed to organic environmental pollutants. Archives of Environmental Contamination and Toxicology, 53(1):110-118. http://www.citeulike.org/user/HEIRS/article/1447133

Arsenescu, V., Arsenescu, R. I., King, V., Swanson, H., and Cassis, L. A. (2008). Polychlorinated biphenyl-77 induces adipocyte differentiation and proinflammatory adipokines and promotes obesity and atherosclerosis. 116(6). http://www.citeulike.org/user/HEIRS/article/5792101

Specific Types of Fat. American Diabetes Association. Retrieved on September 16, 2009.

Turner, N., Hariharan, K., TidAng, J., Frangioudakis, G., Beale, S. M., Wright, L. E., Zeng, X. Y., Leslie, S. J., Li, J.-Y., Kraegen, E. W., Cooney, G. J., and Ye, J.-M. (2009). Enhancement of muscle mitochondrial oxidative capacity and alterations in insulin action are lipid species-dependent: Potent tissue-specific effects of medium chain fatty acids. Diabetes. http://www.citeulike.org/user/HEIRS/article/5792208

(2009). How coconut oil could help reduce the symptoms of type 2 diabetes. Medical News Today. http://www.citeulike.org/user/HEIRS/article/5793232

Coconut Oil. Wipedia. Retrieved on September 16, 2009.

Tasty Foods Send Signal to Brain to Keep Eating. US News. Retrieved on September 16, 2009.

Fatty Liver. Wipedia. Retrieved on September 16, 2009.

Keith Ott, O., Jack Dempse, Y., Richar, D., Beckman, N., and Anne Reifel Mille, R. Aicar reverses the effect of palmitate on metabolic gene expression and mitochondrial number in muscle cells and adipocytes. http://www.citeulike.org/user/HEIRS/article/5793413

Bradley, R. L., Fisher, F. F., and Maratos-Flier, E. (2008). Dietary fatty acids differentially regulate production of tnf-alpha and il-10 by murine 3t3-l1 adipocytes. Obesity (Silver Spring, Md.), 16(5):938-944. http://www.citeulike.org/user/HEIRS/article/5791246

Törmä, H., Geijer, S., Gester, T., Alpholm, K., Berne, B., and Lindberg, M. (2006). Variations in the mrna expression of inflammatory mediators, markers of differentiation and lipid-metabolizing enzymes caused by sodium lauryl sulphate in cultured human keratinocytes. Toxicology in vitro : an international journal published in association with BIBRA, 20(4):472-479. http://www.citeulike.org/user/HEIRS/article/5793447

Helyar, S. G., Patel, B., Headington, K., El-Assal, M., Chatterjee, P. K., Pacher, P., and Mabley, J. G. (2009). Pcb-induced endothelial cell dysfunction: role of poly (adp-ribose) polymerase. Biochemical pharmacology. http://www.citeulike.org/user/HEIRS/article/5041282

Chatterjee, V. K. K. (2001). Ppar gamma and human insulin resistance. In Society for Endocrinology Annual Meeting 2001. BioScientifica. http://www.citeulike.org/user/HEIRS/article/5793459

Yamauchi, T., Kamon, J., Waki, H., Terauchi, Y., Kubota, N., Hara, K., Mori, Y., Ide, T., Murakami, K., Tsuboyama-Kasaoka, N., Ezaki, O., Akanuma, Y., Gavrilova, O., Vinson, C., Reitman, M. L., Kagechika, H., Shudo, K., Yoda, M., Nakano, Y., Tobe, K., Nagai, R., Kimura, S., Tomita, M., Froguel, P., and Kadowaki, T. (2001). The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nature Medicine, 7(8):941-946. http://www.citeulike.org/user/HEIRS/article/5793464

Keith Ott, O., Jack Dempse, Y., Richar, D., Beckman, N., and Anne Reifel Mille, R. Aicar reverses the effect of palmitate on metabolic gene expression and mitochondrial number in muscle cells and adipocytes. http://www.citeulike.org/user/HEIRS/article/5793413

Corcoran, M. P., Lamon-Fava, S., and Fielding, R. A. (2007). Skeletal muscle lipid deposition and insulin resistance: effect of dietary fatty acids and exercise. Am J Clin Nutr, 85(3):662-677. http://www.citeulike.org/user/HEIRS/article/5791465

Törmä, H. and Berne, B. (2009). Sodium lauryl sulphate alters the mrna expression of lipid-metabolizing enzymes and ppar signalling in normal human skin in vivo. Experimental dermatology. http://www.citeulike.org/user/HEIRS/article/4787882

Harrison, K. (2007). Lauric acid @ 3dchem.com. http://www.citeulike.org/user/HEIRS/article/5793491

Turner, N., Hariharan, K., TidAng, J., Frangioudakis, G., Beale, S. M., Wright, L. E., Zeng, X. Y., Leslie, S. J., Li, J.-Y., Kraegen, E. W., Cooney, G. J., and Ye, J.-M. (2009). Enhancement of muscle mitochondrial oxidative capacity and alterations in insulin action are lipid species-dependent: Potent tissue-specific effects of medium chain fatty acids. Diabetes. http://www.citeulike.org/user/HEIRS/article/5792208

Kim, E., Kim, S., Nam, G. W., Lee, H., Moon, S., and Chang, I. (2009). The alkaline ph-adapted skin barrier is disrupted severely by sls-induced irritation. International journal of cosmetic science, 31(4):263-269. http://www.citeulike.org/user/HEIRS/article/5117257

Mateljan, George.The World's Healthiest Foods. Essential Guide for the Healthiest Way of Eating. George Mateljan Foundation. 2007. pg 55.

Sepp, Dennis, PhD. Sodium Lauryl Sulfate - The Straight Story. Retrieved on September 16, 2009.

Bueno, A. A. A., Oyama, L. M. M., de Oliveira, C., Pisani, L. P. P., Ribeiro, E. B. B., Silveira, V. L. F. L., and Oller do Nascimento, C. M. M. (2008). Effects of different fatty acids and dietary lipids on adiponectin gene expression in 3t3-l1 cells and c57bl/6j mice adipose tissue. Pflügers Archiv : European journal of physiology, 455(4):701-709. http://www.citeulike.org/user/HEIRS/article/5780642

Granholm, A.-C. C., Bimonte-Nelson, H. A., Moore, A. B., Nelson, M. E., Freeman, L. R., and Sambamurti, K. (2008). Effects of a saturated fat and high cholesterol diet on memory and hippocampal morphology in the middle-aged rat. Journal of Alzheimer's disease : JAD, 14(2):133-145. http://www.citeulike.org/user/HEIRS/article/5780645

Palomer, X., Alvarez-Guardia, D., Rodriguez-Calvo, R., Coll, T., Laguna, J. C., Davidson, M. M., Chan, T. O., Feldman, A. M., and Vazquez-Carrera, M. (2009). Tnf-alpha reduces pgc-1alpha expression through nf-kappab and p38 mapk leading to increased glucose oxidation in a human cardiac cell model. Cardiovasc Res, 81(4):703-712. http://www.citeulike.org/user/HEIRS/article/4594676

Bonnard, C., Durand, A., Peyrol, S., Chanseaume, E., Chauvin, M. A., Morio, B., Vidal, H., and Rieusset, J. (2008). Mitochondrial dysfunction results from oxidative stress in the skeletal muscle of diet-induced insulin-resistant mice. The Journal of clinical investigation, 118(2):789-800. http://www.citeulike.org/user/HEIRS/article/3152490

Rutkowski, J. M., Davis, K. E., and Scherer, P. E. (2009). Mechanisms of obesity and related pathologies: The macro- and microcirculation of adipose tissue. FEBS Journal, 9999(9999). http://www.citeulike.org/user/HEIRS/article/5795717

Nonalcoholic fatty liver disease. Mayo Clinic. Retrieved on September 16, 2009.

Wieckowski, M. (2000). Long-chain fatty acids promote opening of the reconstituted mitochondrial permeability transition pore. FEBS Letters, 484(2):61-64. http://www.citeulike.org/user/HEIRS/article/5797786

Korge, P., Honda, H. M., and Weiss, J. N. (2003). Effects of fatty acids in isolated mitochondria: implications for ischemic injury and cardioprotection. Am J Physiol Heart Circ Physiol, 285(1):H259-269. http://www.citeulike.org/user/HEIRS/article/5797780

Belisle, S. E., Leka, L. S., Delgado-Lista, J., Jacques, P. F., Ordovas, J. M., and Meydani, S. N. N. (2009). Polymorphisms at cytokine genes may determine the effect of vitamin e on cytokine production in the elderly. The Journal of nutrition. http://www.citeulike.org/user/HEIRS/article/5800741

Hargrave, K. M., Azain, M. J., and Miner, J. L. (2005). Dietary coconut oil increases conjugated linoleic acid-induced body fat loss in mice independent of essential fatty acid deficiency. Biochimica et biophysica acta, 1737(1):52-60.  http://www.citeulike.org/user/HEIRS/article/5800784

Lauric acid. RX List. Retrieved on September 17, 2009.

Yoshinari, K., Okino, N., Sato, T., Sugatani, J., and Miwa, M. (2006). Induction of detoxifying enzymes in rodent white adipose tissue by aryl hydrocarbon receptor agonists and antioxidants. Drug Metab Dispos, 34(7):1081-1089. http://www.citeulike.org/user/HEIRS/article/783432

Liang, H. and Ward, W. F. (2008). Pgc-1: a key regulator of energy metabolism. http://www.citeulike.org/user/HEIRS/article/5805611

Olive Chemistry- The Olive Oil Source. Retrieved on September 17, 2009

Nicholls, S. J., Lundman, P., Harmer, J. A., Cutri, B., Griffiths, K. A., Rye, K.-A. A., Barter, P. J., and Celermajer, D. S. (2006). Consumption of saturated fat impairs the anti-inflammatory properties of high-density lipoproteins and endothelial function. Journal of the American College of Cardiology, 48(4):715-720. http://www.citeulike.org/user/HEIRS/article/5805848

Coghlan, A. (2009). Fat reprograms genes linked to diabetes. NewScientist. http://www.citeulike.org/user/HEIRS/article/5831238

Applied physiology, nutrition, and metabolism = Physiologie appliquée, nutrition et métabolisme, Vol. 33, No. 5. (October 2008), pp. 843-862.

Abdollahi, M., Donyavi, M., Pournourmohammadi, S., and Saadat, M. (2004). Hyperglycemia associated with increased hepatic glycogen phosphorylase and phosphoenolpyruvate carboxykinase in rats following subchronic exposure to malathion. Comparative biochemistry and physiology. Toxicology & pharmacology : CBP, 137(4):343-347.  http://www.citeulike.org/user/HEIRS/article/2988987

Rezg, R., Mornagui, B., El-Fazaa, S., and Gharbi, N. (2008). Caffeic acid attenuates malathion induced metabolic disruption in rat liver, involvement of acetylcholinesterase activity. Toxicology, 250(1):27-31. http://www.citeulike.org/user/HEIRS/article/5831958